spontaneous regression and resolution of breast …...& daniel fleming...
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ORIGINAL ARTICLE BREAST SURGERY
Spontaneous Regression and Resolution of Breast Implant-Associated Anaplastic Large Cell Lymphoma: Implicationsfor Research, Diagnosis and Clinical Management
Daniel Fleming1 • Jason Stone2 • Patrick Tansley3
Received: 5 November 2017 / Accepted: 17 December 2017 / Published online: 14 February 2018
� The Author(s) 2018. This article is an open access publication
Abstract
Background First described in 1997, breast implant-asso-
ciated anaplastic large cell lymphoma (BIA-ALCL) was
recognised by the World Health Organisation in 2016 as a
specific disease. It typically presents as a late seroma-
containing atypical, monoclonal T cells which are CD30?
and anaplastic lymphoma kinase negative. Until recently, it
was thought that the disease was very rare. However, it is
being diagnosed increasingly frequently with 56 cases
confirmed in Australia by September 2017 and the esti-
mated incidence revised from 1 in 300,000 to between 1 in
1000 and 1 in 10,000 patients with bilateral implants. There
is debate about the spectrum of BIA-ALCL. According to
the current WHO classification, BIA-ALCL is a cancer in
all cases. Treatment guidelines require that it is treated
urgently with a minimum of bilateral removal of implants
and capsulectomies. Whilst acknowledging the disease has
been under diagnosed in the past, with some notable ex-
ceptions the BIA-ALCL literature has given scant attention
to the epidemiological evidence. Now that it is known that
the disease may occur in up to 1 in 1000 patients with a
median of 7.5 years from implantation to diagnosis,
understanding it in its epidemiological context is impera-
tive. The epidemiology of cancer and lymphoma in women
with breast implants strongly suggests that most patients do
not have a cancer that will inevitably progress without
treatment but instead a self-limiting lympho-proliferative
disorder. Although the possibility of spontaneous regres-
sion has been raised and the observation made that treat-
ment delay did not seem to increase the risk of spread, the
main objection to the lympho-proliferative hypothesis has
been the lack of documented cases of spontaneous
regression or resolution. Because all cases currently are
considered malignant and treated urgently, only case report
evidence, interpreted in the proper epidemiological con-
text, is likely to be available to challenge this thinking.
Methods and Results New observations and interpretation
of the epidemiology of BIA-ALCL are made. These are
supported by the presentation of two cases, which to the
best of our knowledge comprise the first documented evi-
dence of spontaneous regression and spontaneous resolu-
tion of confirmed BIA-ALCL.
Conclusions The epidemiology of the disease strongly
suggests that the vast majority of cases are not a cancer that
will inevitably progress without treatment. The findings
presented in the manuscript provide supportive clinical
evidence. Consequently, an alternative view of BIA-ALCL
with implications for research, diagnosis and clinical
management needs to be considered.
Level of Evidence IV This journal requires that authors
assign a level of evidence to each article. For a full
description of these Evidence-Based Medicine ratings,
please refer to the Table of Contents or the online
Instructions to Authors www.springer.com/00266.
Keywords BIA-ALCL � Epidemiology � Spontaneous �Regression � Resolution
& Daniel Fleming
1 Cosmetic Surgery Institute of Australia, PO Box 213,
Fortitude Valley, Brisbane, QLD 4006, Australia
2 QML Pathology, 1 Riverview Place, Metroplex on Gateway,
Murarrie, QLD 4172, Australia
3 NorthEast Plastic Surgery, Wickham House, Level 1 155
Wickham Terrace, Spring Hill, Brisbane, QLD 4000,
Australia
123
Aesth Plast Surg (2018) 42:672–678
https://doi.org/10.1007/s00266-017-1064-z
Introduction
First described in 1997, breast implant-associated
anaplastic large cell lymphoma (BIA-ALCL) was recog-
nised by the World Health Organisation in 2016 as a
specific disease [1, 2]. It typically presents as a late seroma-
containing atypical, monoclonal T cells which are CD30?
and anaplastic lymphoma kinase (ALK)-. Until recently, it
was thought that the disease was very rare [3]. However, it
is being diagnosed increasingly frequently with 56 cases
confirmed in Australia by September 2017 and the esti-
mated incidence revised from 1 in 300,000 to between 1 in
1000 and 1 in 10,000 patients with bilateral implants [4, 5].
There is debate about the spectrum of BIA-ALCL [6, 7].
According to the current WHO classification, BIA-ALCL
is a cancer in all cases. Treatment guidelines require it is
treated urgently with a minimum of bilateral removal of
implants and capsulectomies [8]. Whilst acknowledging
the disease has been under diagnosed in the past [8], with
some notable exceptions the BIA-ALCL literature has
given scant attention to the epidemiological evidence
[9, 10]. Now that it is known that the disease may occur in
up to 1 in 1000 patients with a median of 7.5 years from
implantation to diagnosis, understanding it in its epidemi-
ological context is imperative [5, 11]. The epidemiology of
cancer and lymphoma in women with breast implants
strongly suggests that most patients do not have a cancer
that will inevitably progress without treatment but instead a
self-limiting lympho-proliferative disorder [12–17].
Although the possibility of spontaneous regression has
been raised and the observation made that treatment delay
did not seem to increase the risk of spread [9], the main
objection to the lympho-proliferative hypothesis has been
the lack of documented cases of spontaneous regression or
resolution. Because all cases currently are considered
malignant and treated urgently, only case report evidence,
interpreted in the proper epidemiological context, is likely
to be available to challenge this thinking.
Materials, Methods and Results
We reviewed the available epidemiology and present two
cases, which to the best of our knowledge comprise the first
documented evidence of spontaneous regression and
spontaneous resolution of confirmed BIA-ALCL.
Case 1: Spontaneous Regression
In 1994, a 32-year-old female underwent bilateral, subg-
landular breast augmentation and concomitant periareolar
mastopexy using Mentor (Mentor Corp., Santa Barbara,
CA), smooth, saline implants. A left sided post-operative
wound infection was treated conservatively. She developed
bilateral capsular contracture after some months.
In 2009, she underwent bilateral explantation and
replacement with Silimed (Silimed, Rio de Janeiro), poly-
urethane foam-covered silicone gel implants in new sub-
muscular pockets. The left capsule was heavily calcified
and excised; the right capsule was retained. Her recovery
was uneventful.
In May 2014, aged 51, she presented to her GP with a
unilateral enlargement of the right breast. An ultrasound
scan demonstrated the presence of a large seroma. She
delayed seeking treatment for 8 months until January 2015
when she underwent aspiration. Cytology was diagnostic
for BIA-ALCL with abundant atypical T cells that were
CD30? and ALK- (Figs. 1, 2). Culture was negative.
Subsequent bone marrow aspirate, blood investigations and
PET scan were normal. Two months later in March 2015,
the aspiration was repeated. Most of the cells identified
were benign macrophages and flow cytometry was normal.
The very scant CD30? cells identified (Fig. 3) were
interpreted as representing a combination of benign acti-
vated lymphocytes, a recognised phenomenon [18–20] and
very low level of lymphoma (\ 5%). One month later
in April 2015, she underwent breast implant explantation
and capsulectomy. At surgery, occasional atypical lym-
phoid cells were identified on cytological examination of
the greatly reduced residual seroma fluid (Fig. 4). The fluid
was paucicellular, and there was insufficient cellular
material for reliable immunohistochemical examination.
Flow cytometry was non-diagnostic. Widely sampled
Fig. 1 Case 1. Seroma cytology January 2015. Giemsa stain 9400.
All the larger cells seen are tumour cells. Atypical cytological
features include abundant finely vacuolated cytoplasm, marked
nuclear pleomorphism, irregular nuclear membranes and polylobu-
lated nuclei. A normal small lymphocyte (arrowed) allows easy
comparison. The background comprises erythrocytes
Aesth Plast Surg (2018) 42:672–678 673
123
histopathology of the capsule was normal, and capsular
CD30 was negative (Fig. 5). The patient has since
remained asymptomatic.
Case 2: Spontaneous Resolution
In February 2017, a 24-year-old female complained of a
sudden enlargement of her left breast. She had had an
uncomplicated primary breast augmentation with Silimed
polyurethane foam-covered silicone gel filled implants in
submuscular pockets in May 2013. An ultrasound reported
a seroma with an estimated volume of 50 cc. Aspiration
was performed 10 days later. The estimated volume was
again 50 cc, but a total of 80 cc was drained. Cytology and
immunohistochemistry confirmed BIA-ALCL with atypi-
cal T cells which were CD30? and ALK- (Figs. 6, 7).
Culture of the fluid was negative. The patient had no fur-
ther symptoms. Haematological investigations and a PET
scan were normal. The patient was informed that she had a
malignancy and underwent bilateral explantation and cap-
sulectomies on 5 May 2017, 10 weeks after the onset of her
symptoms. Cytology, flow cytometry and
Fig. 2 Case 1. Cell block of seroma fluid January 2015. Haema-
toxylin & Eosin 9100. This lower power magnification demonstrates
the marked cellularity of the sample. The inserts show that virtually
every cell is positive for CD30 and negative for CD163 (a
macrophage marker)
Fig. 3 Case 1. Cell block of seroma fluid March 2015. Haematoxylin
& Eosin 9100. The inserts show that now there are only scant CD30
positive cells and that most of the cells are CD163 positive benign
macrophages
Fig. 4 Case 1. Seroma cytology April 2015. Giemsa stain 9400. The
fluid is remarkably more paucicellular than previous samples. This
photomicrograph shows only scant larger cells with background
cellular debris and a few small benign lymphocytes, indicating very
low level of residual lymphoma. The sample was too paucicellular for
a cell block
Fig. 5 Case 1. Histological section of the implant capsule April
2015. Haematoxylin & Eosin 9100. There is a bland fibrous capsule
with occasional reactive lymphoid aggregate (arrowed) and areas of
pseudosynovial metaplasia. No capsular lymphoma is present. The
inset shows that the reactive lymphoid aggregates are negative for
CD30
674 Aesth Plast Surg (2018) 42:672–678
123
immunohistochemistry of a small residual fluid collection,
and histopathology of the capsule, showed no evidence of
malignancy (Figs. 8, 9). The patient has remained asymp-
tomatic, and a repeat PET scan on 5 July 2017 was normal.
The slides from both cases were sent for external expert
review which confirmed the initial diagnoses and subse-
quent findings.
Discussion
The first known case of BIA-ALCL in Australia was
diagnosed in 2007, but recently a rapidly rising incidence
has been reported [11]. Forty-six cases had been reported
by December 2016 in Australia [5], but by September 2017
further 10 cases had been confirmed with 2 more under
investigation [4, 21]. The absence of disease in the
explanted capsule has not been classified as spontaneous
resolution, and seroma-only disease is still classified as a
stage 1 malignancy [2]. Relevantly, until recently only
capsular tissue and not seroma fluid was submitted for
analysis at explantation [22]. Thus, other cases of
Fig. 6 Case 2. Seroma cytology from aspiration on 7 March 2017.
Giemsa stain 9400. All the larger cells seen are tumour cells. A
normal small lymphocyte (arrowed) allows easy comparison. The
insert shows the CD4 positivity
Fig. 7 Case 2. Seroma cytology from aspiration on 7 March 2017.
Papanicolaou stain 9400. The insert shows the positive CD30 and
negative ALK–1 immunocytochemistry
Fig. 8 Case 2. Peri-implant fluid at explant on 5 May 2017.
Papanicolaou stain 9400. Benign foamy macrophages are present
(CD30 negative). No lymphoma cells are seen
Fig. 9 Case 2. Histological section of the removed implant capsule at
explantation on 5 May 2017. Haematoxylin & Eosin 9100. There is
benign pseudosynovial metaplasia (black arrow) and foreign body
reaction to silicone material (red arrow). No lymphoma is seen
Aesth Plast Surg (2018) 42:672–678 675
123
spontaneous regression or resolution may have been mis-
sed. For example, the case of spontaneous resolution pre-
sented here would have been missed had the small,
asymptomatic residual seroma fluid not been analysed at
explantation. The case presented of spontaneous regression
is unique because 7 months elapsed from first presentation
and confirmation of seroma to the diagnosis being made on
aspiration. Also, there was a further 4-month delay before
the patient consented to surgical management. Therefore,
11 months elapsed from her presentation with late seroma
to surgical explantation. The case has presented us with an
opportunity to follow the natural history of BIA-ALCL for
almost 1 year. Until and unless treatment guidelines
change, it is unlikely to be repeated as patients with con-
firmed disease are now treated more expediently.
The case of spontaneous resolution occurred within
10 weeks of the patient first having symptoms and 8 weeks
after the confirmed diagnosis of BIA-ALCL. This not only
proves that the disease can spontaneously resolve but also
that it can do so rapidly. The case allows us to reflect on the
consequences of the changed management of seroma
patients which is based on our relatively new and limited
knowledge of BIA-ALCL. Previously, this patient, fol-
lowing a single aspiration and no further symptoms, would
not have received any further treatment and would have
been diagnosed as a simple seroma. With a symptomatic
seroma, estimated as 50 cc on an ultrasound scan, she may
or may not have had an aspiration at all. If she did, the fluid
would not have been subjected to cytological examination.
She would likely have been given antibiotics, and she
would not have had any more symptoms just as she did not
have any following the diagnosis of BIA-ALCL.
All confirmed BIA-ALCL patients in Australia were
exposed to textured or polyurethane covered implants [11].
The median time from implantation to diagnosis was
7.5 years, and 90% of the cases had occurred by 14 years
[5, 11]. Textured implants have been widely, and increas-
ingly, used in Australia since 1991 yet the first case in
Australia was not recognised until 16 years later. The
testing of late seromas for cytology did not commence until
2008 and has become increasingly common since. There is
no reason to suppose that BIA-ALCL was not present with
the same incidence in textured-implant-related late seromas
prior to the advent of cytological testing as afterwards. This
begs the question, where are the cases which should have
been diagnosed in the interim? Cancer registry data have
shown no increase in the incidence of non-Hodgkin lym-
phoma in women in the period 2000–2013 [23]. The
existence of spontaneous regression and spontaneous res-
olution explains what happened to the seroma patients who
had undiagnosed BIA-ALCL prior to the onset of cyto-
logical testing to look for it—they got better, often without
surgical intervention [24, 25]. The inescapable conclusion
is that the rapid and accelerating rise in the diagnosis of
BIA-ALCL in Australia is just that—a rise in the diagnosis
of the disease, not a rise in its incidence. This would not be
unique. Observing the more than sixfold increase in the
diagnosis of thyroid cancer without a change in mortality
following the onset of screening in South Korea, the
authors concluded, ‘‘over detection of clinically indolent
thyroid cancers is the best explanation for the observed
findings in our study’’ [26].
These findings may not be unexpected as a pathological
precedent for spontaneous resolution of a similar disease
already exists. The spectrum disorder lymphomatoid
papulosis and primary cutaneous ALCL is a rare skin
disorder that is considered histologically malignant but
often clinically benign [27]. Lesions contain atypical T
cells that are also CD30? and ALK-, as with BIA-ALCL
[28]. The disease, which has been recognised since 1968,
behaves similarly to BIA-ALCL in that it spreads infre-
quently and has an excellent prognosis. Importantly, it can
spontaneously resolve, even in the primary cutaneous
ALCL form [29].
In conjunction with the observed epidemiology of this
disease, these findings have implications for how we con-
sider BIA-ALCL.
• At least two types of BIA-ALCL appear to exist—non-
invasive seroma-only disease that typically sponta-
neously resolves or remains indolent and a much rarer
invasive malignant disease, usually with a mass present
at diagnosis, which does not [7, 14].
• In Australia, the proportion of patients who have
seroma-only disease with no evidence of capsular
involvement is now 70% and rising as more cases are
diagnosed [21].
• Seroma-only BIA-ALCL should be more accurately
described as a lympho-proliferative disorder rather than
a malignant lymphoma. Our findings add supportive
clinical evidence to the calls others have made, on a
mortality basis, for an immediate revision of the WHO
classification [30].
• Do any seroma-only cases become invasive and can we
develop a method to identify truly seroma-only disease
without surgery?
• Although falling, currently 30% of cases have some
disease in the capsule. In the absence of a mass, is
progression inevitable without treatment? These data
and the epidemiological evidence suggest otherwise.
Given the potentially fatal consequences of inadequate
treatment, and the present inability to be certain that the
disease is not invasive without histopathology, bilateral
explantation and capsulectomies should remain the current
recommended minimum treatment. However, it should be
also acknowledged this may be overtreatment for many
676 Aesth Plast Surg (2018) 42:672–678
123
patients. In this context, we note that of the four deaths
attributed to BIA-ALCL in Australia, two were caused by
complications of the aggressive treatment that was initially
thought to be necessary for all patients [11]. The historical
harmful overtreatment of other malignancies, for example
prostate cancer and neuroblastoma, has been established
and, with increasing knowledge, more conservative
strategies safely implemented [31, 32].
The primary goal remains the safe treatment of BIA-
ALCL. A method to identify the majority of patients who
may be safely managed without surgery, as they were in
the past, from the few who cannot, is needed. Further
analysis of seroma-only disease from a clinical, cytological
and epidemiological perspective should be a priority. It is
through a better understanding of the natural history of the
spectrum of this disease that we will be able to advise
correctly and apply more appropriate therapy for the
increasing number of women with this diagnosis, ensuring
the vast majority are not told, incorrectly, they have cancer.
Conclusions
The epidemiology of the disease strongly suggests that the
vast majority of cases are not a cancer that will inevitably
progress without treatment. The findings presented in the
manuscript provide supportive clinical evidence and
emphasise the importance of analysing seroma fluid as well
as the capsule at explantation. An alternative view of BIA-
ALCL with implications for research, diagnosis and clini-
cal management needs to be considered.
Acknowledgements The authors wish to thank Dr. Roberto Miranda
at the MD Anderson Cancer Centre, for his review of the slides of
both cases, and Dr. Linda Shen at Pathology Queensland, for her
assistance with the case of spontaneous resolution.
Compliance with Ethical Standards
Conflict of interest The first author has previously acted as a con-
sultant to the Silimed Corporation. All other authors have no conflicts
of interest to disclose.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
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